JPS5980683A - 6-fluoro-1,8-naphthyridine derivative and its preparation - Google Patents
6-fluoro-1,8-naphthyridine derivative and its preparationInfo
- Publication number
- JPS5980683A JPS5980683A JP57191594A JP19159482A JPS5980683A JP S5980683 A JPS5980683 A JP S5980683A JP 57191594 A JP57191594 A JP 57191594A JP 19159482 A JP19159482 A JP 19159482A JP S5980683 A JPS5980683 A JP S5980683A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- boron trifluoride
- fluoro
- compound
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- QILHGSSOWXKYFZ-UHFFFAOYSA-N 3-fluoro-1,8-naphthyridine Chemical class N1=CC=CC2=CC(F)=CN=C21 QILHGSSOWXKYFZ-UHFFFAOYSA-N 0.000 title abstract description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 229910015900 BF3 Inorganic materials 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 239000013522 chelant Substances 0.000 claims description 10
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical group C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- XJDDLMJULQGRLU-UHFFFAOYSA-N 1,3-dioxane-4,6-dione Chemical compound O=C1CC(=O)OCO1 XJDDLMJULQGRLU-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 claims 1
- 150000005054 naphthyridines Chemical class 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 abstract description 8
- 238000010438 heat treatment Methods 0.000 abstract description 3
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract description 2
- DJDDYWYYTKNZPM-UHFFFAOYSA-N 2-amino-1,3-dioxane-4,6-dione Chemical compound NC1OC(=O)CC(=O)O1 DJDDYWYYTKNZPM-UHFFFAOYSA-N 0.000 abstract 1
- UGIDCIOQJBCTOE-UHFFFAOYSA-N 7-(4-ethoxycarbonylpiperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1CN(C(=O)OCC)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2CC UGIDCIOQJBCTOE-UHFFFAOYSA-N 0.000 abstract 1
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 239000002738 chelating agent Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003513 alkali Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical group N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000006203 ethylation Effects 0.000 description 2
- 238000006200 ethylation reaction Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical class CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- YUMCAWUAVINQTG-UHFFFAOYSA-N 2-fluoro-1,8-naphthyridine Chemical class C1=CC=NC2=NC(F)=CC=C21 YUMCAWUAVINQTG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 150000001987 diarylethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- -1 sodium and potassium Chemical class 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は１−エチル−６−フルオロ−１，４−ジヒドロ
−４−オキソ−７−（４−エトキシカルボニル−１−ヒ
。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethoxycarbonyl-1-h).
ベラシニル）−１，８−ナフチリジン−６−カルボン酸
ＢＰ キレート化合物（以下、ＢＦ２キレート化合物
という）およびその製造法ならびにＢＩ”２キレ一ト化
合物を加水分解することにより１−エチル−６−フルオ
ロ−１，４−ジヒドロ−４−オキソ−（１−ヒ°ペラジ
ニル）−１，８−ナフチリジン−６−カルボン酸を製造
する方法に関する。さらに詳しくは式（■）：であられ
される化合物および式（■）：であられされるジエチル
−Ｎ−エチル−Ｎ−（２−（４−エトキシカルボニル−
１−ピペラジニル）−３−フルオロ−６−ピリジルコア
ミノメチレンマロネートを三フッ化ホウ素および（また
は）三フッ化ホウ素錯体を用いて環化縮合させることを
特徴とする前記式（Ｉ）であられされる化合物の製造法
ならびに前記ＢＦ２キレート化合物な加水分解すること
を特徴とする式（■）：
であられされる１−エチル−６−フルオロ−１，４−ジ
ヒドロ−４−オキソ−７−（１−ピペラジニル）−１，
８−ナフチリジン−６−カルボン酸の製造法に関する。Veracinyl)-1,8-naphthyridine-6-carboxylic acid BP chelate compound (hereinafter referred to as BF2 chelate compound) and its production method, and 1-ethyl-6-fluoro- It relates to a method for producing 1,4-dihydro-4-oxo-(1-hyperazinyl)-1,8-naphthyridine-6-carboxylic acid.More specifically, it relates to a method for producing 1,4-dihydro-4-oxo-(1-hyperazinyl)-1,8-naphthyridine-6-carboxylic acid. ■): diethyl-N-ethyl-N-(2-(4-ethoxycarbonyl-
1-Piperazinyl)-3-fluoro-6-pyridylcoamino methylene malonate is cyclized and condensed using boron trifluoride and/or a boron trifluoride complex. 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-( 1-piperazinyl)-1,
The present invention relates to a method for producing 8-naphthyridine-6-carboxylic acid.
式（ｌＩｌ）であられされる化合物は抗菌剤としての賭
性質が公知の抗菌作用を有する化合物（特開昭５５−８
５７８５号公報参照）の中でも優れており、きわめて有
用な化合物である。また式ＣＩ）であられされる化合物
は新規化合物であり、前記式（，１１１）であられされ
る６−フルオロ−１，８−ナフチリジン誘導体へのきわ
めて適切な前駆体である。The compound represented by the formula (lIl) is a compound having antibacterial activity known for its properties as an antibacterial agent (Japanese Patent Laid-Open No. 55-8
5785) and is an extremely useful compound. The compound of formula CI) is also a new compound and is a very suitable precursor to the 6-fluoro-1,8-naphthyridine derivative of formula (,111).
式（ｍ）であられされる化合物の製造法として特公昭−
５７−１０１０９号公報に次式に示すごとく、化合物（
Ａ）を加熱閉環せしめ、ついでヨウ化エチルでエチル化
し、生成した化合物（０）を加水分解することにより目
的の化合物ＦＤ）をうる報告がなされている。As a method for producing the compound represented by formula (m),
No. 57-10109 discloses a compound (
It has been reported that the target compound FD) can be obtained by ring-closing A) by heating, then ethylating it with ethyl iodide, and hydrolyzing the resulting compound (0).
（Ａ）、 （Ｂ）（
０） （Ｄ）しか
し前記式（ＩＩ）であられされる化合物を環化縮合させ
、相当する１、８−ナフチリジン環を形成せしめる例は
得られる式（Ｉ）の化合物およびその製造法ともこれま
で知られてぃなかった。(A), (B)(
0) (D) However, the example of cyclization condensation of the compound represented by the above formula (II) to form the corresponding 1,8-naphthyridine ring has not been described previously with respect to the resulting compound of formula (I) and its production method. It wasn't known.
本発明者らは前記式（［）であられされる化合物を三フ
ッ化ホウ素および（またはン三７ツ化ホウ、１体と加熱
することにより容易に１．８−ナフチリジン環を形成す
ることを見出し、すなわち式（損であられされる化合物
を三７〕化ホウ素および（または）三フッ化ホウ素錯体
を用いて溶媒の存在下または非存在下に加熱環化縮合せ
しめることにより、式（１）であられされる新規な化合
物を容易にえられることおよび該化合物を加水分解する
ことによりすぐれた収率で抗菌剤として有用な式（Ｉｌ
ｌ）であられされる化合物、１−エチル−６−フルオロ
−１，４−ジヒド四−４−オキソ−７−（１−ピペラジ
ニル）−１，８−ナフチリジン−６−カルボン酸を容易
にえられることを見出し、本発明を完成するにいたった
。The present inventors have found that a 1,8-naphthyridine ring can be easily formed by heating the compound represented by the above formula ([) with boron trifluoride and boron trifluoride (or boron trifluoride). Formula (1) can be obtained by subjecting a compound represented by the formula (1) to thermal cyclization condensation using boron trifluoride and/or a boron trifluoride complex in the presence or absence of a solvent. The novel compounds of the formula (Il
The compound prepared by l), 1-ethyl-6-fluoro-1,4-dihydro-4-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-6-carboxylic acid, can be easily obtained. This discovery led to the completion of the present invention.
本発明に用いる原料物質である式（ｎ）であられされる
化合物は新規化合物であり次式の工程で製箔されうる。The compound represented by formula (n), which is a raw material used in the present invention, is a new compound and can be produced into foil by the following process.
前記の様に従来法による環化生成物（Ｂ）はその１位が
未だエチル化されておらず、さらにエチル化の工程を必
要とする。これに対し、本発明に用いる原料物質である
（…）であられされる化合物は２，６−ジクロルピリジ
ンのエチルアミノ化工程を経て製造されるため、これを
環化縮合させた式（Ｉ）であられされる化合物の１位に
はすでにエチル基が導入されており、化合物（Ａ）を原
料物質とする従来法のごとくさらにエチル化する工程は
不要である。しかも２，６−ジクロルピリジンのエチル
アミンによるエチルアミノ化はアンモニア水による単な
るアミノ化と比較して１４０°０（〜９ ｋｇ／ｃｍ”
） ６時間、収率９３％というはるかに容易な条件で
、かつ高収率で製造することができるという利点を有す
ることもまた見出している。As mentioned above, the cyclization product (B) obtained by the conventional method has not yet been ethylated at the 1-position and requires an additional ethylation step. On the other hand, since the compound formed by (...), which is the raw material used in the present invention, is produced through the ethylamination step of 2,6-dichloropyridine, it is cyclized and condensed with the formula (I ) An ethyl group has already been introduced into the 1-position of the compound (A), and there is no need for a further ethylation step as in conventional methods using compound (A) as a raw material. Moreover, the ethylamination of 2,6-dichloropyridine with ethylamine is 140°0 (~9 kg/cm") compared to simple amination with aqueous ammonia.
) has also been found to have the advantage of being able to be produced under much easier conditions and with a high yield of 93% in 6 hours.
前記のように式（Ｉｔ）であられされる化合物を用いて
新規な化合物である式（Ｉ）であられされる化合物を容
易に製造し、該化合物より式（Ｊｌｌ）であられさｆ−
Ｌ、６ローフルオロー１．８−ナフチリジン誘導体が化
合物（Ａ）を原料物質とする従来法と比較して極めて有
利に製造される。As described above, a novel compound represented by formula (I) can be easily prepared using a compound represented by formula (It), and from this compound, f-
L,6-low fluoro-1,8-naphthyridine derivatives are produced very advantageously compared to conventional methods using compound (A) as a raw material.
本発明の式（１）の化合物を製造する方法は式（］）で
あられされる化合物と三フッ化ホウ素および（または）
三フッ化ホウ素錯体との混合物を溶媒の存在下で１８０
〜２５０°Ｃ１好ましくは２００〜２４０°０で１〜６
０分間、好ましくは４〜４０分間保持することにより行
なわれる。The method for producing the compound of formula (1) of the present invention includes a compound of formula (]), boron trifluoride and/or
The mixture with boron trifluoride complex was heated to 180 ml in the presence of a solvent.
~250°C1 preferably 200-240°0 and 1-6
This is carried out by holding for 0 minutes, preferably 4 to 40 minutes.
該環化縮合を溶媒の存在下で行なうさいの原料化合物お
よび溶媒の混合法は種々可能であり、たとえば溶媒と式
（ｎ）であられされる化合物とを混合し、所定の温度に
加熱し、それに三フッ化ホウ素を吹き込むかまたは三フ
ッ化ホウ素錯体を添加する、または式（ＩＩ）であられ
される化合物、三フッ化ホウ素錯体および溶媒を室温で
混合し、その混合物をそれとは別に所定の温度に加熱さ
れた溶媒中に滴下する方法などがあげられる。Various methods are possible for mixing the raw material compound and the solvent in which the cyclization condensation is carried out in the presence of a solvent. For example, the solvent and the compound represented by formula (n) are mixed, heated to a predetermined temperature, Bubbling boron trifluoride or adding a boron trifluoride complex thereto, or mixing the compound of formula (II), the boron trifluoride complex and the solvent at room temperature, and separately dissolving the mixture into a predetermined Examples include a method in which the solution is dropped into a solvent heated to a certain temperature.
本発明において用いる三フフ化ホウ素錯体としては三フ
ッ化ホウ素の環状エーテル錯体、ジアルキルエーテル錯
体などのエーテルＭ体など各種のものが使用できる。た
とえば三フフ化ホウ素のテトラヒドロフラン錯体、ジブ
チルエーテル錯体、ジエチルエーテル錯体などが具体例
としてあげられ、それらは単独または２種以上を混合し
て使用される。かかる三フッ化ホウ素および（または）
三フッ化ホウ素錯体の使用量は式（１）であられされる
化合物１モルに対して１〜６モルの範囲、とくに１〜１
．５モルの範囲が好ましい。本発明において使用される
溶媒としては安定でしかも反応温度を１８０〜２５０°
Ｏに保持するのに充分な沸点を有するものであればとく
に制限されず、ジアリール、ジアリールエーテルなどが
好ましく、たとえばジフェニルエーテルまたはジフェニ
ルエーテルとジフェニルとの混合物などが入手しやすい
などの点から好ましい。溶媒の使用量はとくに制限され
ないが作業能率の面から式（ＩＩ）であられされる化合
物１重量部に対して１５重に部具下の範囲が好ましい。As the boron trifluoride complex used in the present invention, various types can be used, such as a cyclic ether complex of boron trifluoride and an ether M form such as a dialkyl ether complex. Specific examples include tetrahydrofuran complexes, dibutyl ether complexes, and diethyl ether complexes of boron trifluoride, which may be used alone or in combination of two or more. Such boron trifluoride and/or
The amount of boron trifluoride complex used is in the range of 1 to 6 mol, particularly 1 to 1 mol, per 1 mol of the compound represented by formula (1).
．． A range of 5 moles is preferred. The solvent used in the present invention is stable and has a reaction temperature of 180 to 250°.
It is not particularly limited as long as it has a boiling point sufficient to maintain O. Diaryl, diaryl ether, etc. are preferable, and for example, diphenyl ether or a mixture of diphenyl ether and diphenyl is preferable because it is easily available. The amount of the solvent to be used is not particularly limited, but from the viewpoint of work efficiency, it is preferably within the range of 15 parts by weight per 1 part by weight of the compound represented by formula (II).
本発明の方法、すなわち式（Ｉ）であられされるＢＦ２
キレート化合物を加水分解することにより目的とする式
（Ｉｌ［）であられされる化合物、１−エチル−６−フ
ルオロ−１，４−ジヒドロ−４−オキソ−７−（１−ピ
ペラジニル）−１，ａ−ナフチリジン−６−カルボン酸
を収率約９５％という高率でうろことができるが、環化
縮合を溶媒の存在下で行なうばあい、式（Ｉ）であられ
されるＢＦ２キレート化合物を反応液から取出さず、反
応液をそのまま加水分解することもできる。加水分解は
酸処理でも行ないうるが、アルカリ処理が好ましい。加
水分解は水および（または）アルコール中で実施するこ
とができ、本発明にいう加水分解とは水のみならずメタ
ノール、エタノールナトのアルコール中で行なわれる反
応をも含む概念である。アルカリ処理で使用するアルカ
リとしてはとくに限定されないが、工業的に入手しやす
いナトリウム、カリウムなどの水酸化物などがあげられ
る。それらのアルカリの使用量としてはとくに限定され
ないが、たとえば原誉である式（１）であられされる化
合物を１モル用いてたとえば１０％（重量％、以下同様
）苛性ソーダ水溶液で処理するばあいには苛性ソーダ水
溶液を１〜１０！程度使用するのが操作上好ましい。該
処理の温度は５０〜１００°Ｃの範囲で行なうのが好ま
しい。アルカリ処理終了後、酸で中和することにより式
（Ｉｌｌ）であられされる化合物を結晶でうろことがで
きる。The method of the invention, i.e. BF2 prepared by formula (I)
A compound obtained by the desired formula (Il[) by hydrolyzing a chelate compound, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1, Although it is possible to obtain a-naphthyridine-6-carboxylic acid with a high yield of about 95%, when the cyclization condensation is carried out in the presence of a solvent, the BF2 chelate compound of formula (I) is reacted. It is also possible to hydrolyze the reaction solution as it is without removing it from the solution. Although hydrolysis can be carried out by acid treatment, alkali treatment is preferred. Hydrolysis can be carried out in water and/or alcohol, and the concept of hydrolysis in the present invention includes reactions carried out not only in water but also in alcohols such as methanol and ethanol. The alkali used in the alkali treatment is not particularly limited, but includes hydroxides such as sodium and potassium, which are industrially easily available. The amount of the alkali to be used is not particularly limited, but for example, when 1 mole of the compound represented by the formula (1) is used and treated with a 10% (wt%, same hereinafter) aqueous solution of caustic soda. is a caustic soda aqueous solution of 1 to 10! Operationally, it is preferable to use the same amount. The temperature of this treatment is preferably in the range of 50 to 100°C. After the alkali treatment is completed, the compound represented by the formula (Ill) can be obtained as crystals by neutralizing with an acid.
なお本発明において加水分解とは、Ｂ％キレート化合物
をそのＢＦキレート部分のＢＦ２をはずしカルボン酸ま
たはその塩とする反応および７位のヒヘラジン環上の４
位のエトキシカルボニル基の脱１４１を反応をも同時に
行なわしめるものである。In the present invention, hydrolysis refers to the reaction of a B% chelate compound to remove BF2 from its BF chelate moiety to form a carboxylic acid or a salt thereof, and
Removal of the ethoxycarbonyl group at position 141 is also carried out at the same time.
前記のごとく本発明の方法により高収率がっ高能率で式
（Ｉｌｌ）であられされる化合物、１−エチル−６−フ
ルオｔｆｆ−１，４−ジヒドロ−４−オキソ−７−（１
−ピペラジニル）−１，８−ナフチリジン−３−カルボ
ン酔ヲうることかできるので本発明の方法は工業的にき
わめて有利な方法である。As mentioned above, the method of the present invention can be used to produce the compound of formula (Ill) in high yield and efficiency, 1-ethyl-6-fluorotff-1,4-dihydro-4-oxo-7-(1
-Piperazinyl)-1,8-naphthyridine-3-carboxylic acid can be obtained, so the method of the present invention is industrially very advantageous.
つぎに実施例をあげて本発明の化合物および本発明の詳
細な説明する。Next, the compounds of the present invention and the present invention will be explained in detail by giving Examples.
実施例１
ジエチル−Ｎ−エチル−Ｎ−（２−（４−エトキシカル
ボニル−１−ヒ°ベラジニル＞−Ｓ−フルオ四−６−ヒ
°リジル〕アミノメチレンマロネ・−） ４６．６ｇ
、タウサーム（熱媒体、ダウケミカル社製）１４０ｇお
よび三フッ化ホウ素テトラヒドロフラン錯体１５．４９
を室温で混合した。その混合物を２３０ｏＯ付近に加熱
され攪拌されているダウ−リーム２００ｇ中に、反応中
に生じる低１１５点物質を反応系外に溜出させｊｊから
、１ｏ分間かけて滴下した。滴下終了後さらに５分間同
温度に保持した。Example 1 Diethyl-N-ethyl-N-(2-(4-ethoxycarbonyl-1-hyperazinyl>-S-fluoro4-6-hylysyl]aminomethylene malone-) 46.6 g
, Tautherm (thermal medium, manufactured by Dow Chemical Company) 140 g and boron trifluoride tetrahydrofuran complex 15.49 g
were mixed at room temperature. The mixture was added dropwise to 200 g of Dow Ream, which was heated to around 230 oO and stirred, over a period of 1 o minutes, to allow the low 115 point substances produced during the reaction to be distilled out of the reaction system. After the dropwise addition was completed, the same temperature was maintained for an additional 5 minutes.
環化縮合終了後反応液を室温まで冷却し、析出した結晶
を側渦し、石油エーテルで洗浄して１−エチル−７−（
４−エトキシカルボニル−１−ピペラジニル）−６−フ
ルメロ−１，４−ジヒドロ−４−オキソ−１，８−ナフ
チリジン−３−カルボン１浚−ＢＦ２−キレート５９．
６９（収率９ｏ％）をえた。After the completion of the cyclocondensation, the reaction solution was cooled to room temperature, the precipitated crystals were side-vortexed, and washed with petroleum ether to give 1-ethyl-7-(
4-ethoxycarbonyl-1-piperazinyl)-6-flumero-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate-BF2-chelate 59.
69 (yield 9o%) was obtained.
えられた化合物の元素分析、融点測定、ＮＭＲ分析、工
Ｒ分析を行なった結果を以下に示す。The results of elemental analysis, melting point measurement, NMR analysis, and engineering R analysis of the obtained compound are shown below.
元素分析値：
実測値Ｃ％） ： ０４９．０２ Ｈ４，４６Ｎ １
２．４８Ｂ ２．３２ Ｆ １２．８８
理論値（％）！ ｏ ４９．１１ Ｈ４，５８Ｎ １
２．７３Ｂ ２．４６ Ｆ １２．９５
融 点：２７０〜２７５°０（５４９°Ｃで分解）
ＮＭＲ（δ値、ｐｐｍ ） ： ０Ｆ３００ＯＤ中１．
５７ （ｔ、 Ｎ−０Ｈ２−ＯＨ３） 、１．６６ 、
（ｔｓ ０００−ａＨ２＝−ａＨ３）、３．６０〜４．
５０（ｍ、ピペラジン環の水素原子）、４．３５（ｑ
、 Ｎ−０Ｒ２−ＯＨ３）、４．８０ （ｑ、 Ｎ０Ｏ
Ｏ−ＯＨ２−ＯＨ３）、８．１１（ｄ、ナフチリジン環
の５位の水素原子）、９．１６（８％ナフチリジン環の
２位の水Ｍ原子）工Ｒｊ ＫＢｒ法
１６４０ｃｍ （共役カルボニル基）実施例２
ジエチル−Ｎ−エチル−Ｎ−（２−（４−エトキシカル
ボニル−１−ピペラジニル）−３−フルオロ−６−ピリ
ジル〕アミノメチジンマロネー） ４６．６ｇ 、Ｅ
ｙフ化ホウ素テトラヒドロフラン錯体１５．８ｇおよび
ジフェニルエーテルとジフェニルのＪＹｊｊｔ比２．４
：１の混合物ｓｏｐを室温で混合した。その混合物を２
２８〜２３１°０に加熱され、１１押されているジフェ
ニルエーテルとジフェニルト（７）ｆｆｉ量比２．４：
１の混合物１２０９中に、反応中に生じる低沸点物質を
反応系外に溜出させながら、２５分間かけて滴下した。Elemental analysis value: Actual value C%): 049.02 H4,46N 1
2.48B 2.32 F 12.88 Theoretical value (%)! o 49.11 H4,58N 1
2.73B 2.46 F 12.95 Melting point: 270-275°0 (decomposes at 549°C)
NMR (δ value, ppm): 1 in 0F300OD.
57 (t, N-0H2-OH3), 1.66,
(ts 000-aH2=-aH3), 3.60-4.
50 (m, hydrogen atom of piperazine ring), 4.35 (q
, N-0R2-OH3), 4.80 (q, N0O
O-OH2-OH3), 8.11 (d, hydrogen atom at the 5-position of the naphthyridine ring), 9.16 (8% water M atom at the 2-position of the naphthyridine ring) Engineering Rj KBr method 1640 cm (conjugated carbonyl group) carried out Example 2 Diethyl-N-ethyl-N-(2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro-6-pyridyl]aminomethidine maloney) 46.6g, E
y boron fluoride tetrahydrofuran complex 15.8g and JYjjt ratio of diphenyl ether and diphenyl 2.4
:1 mixture sop was mixed at room temperature. 2 of the mixture
Diphenyl ether and diphenyl(7)ffi ratio heated to 28-231°0 and pressed 11: 2.4:
1 into the mixture 1209 over 25 minutes while distilling low-boiling substances generated during the reaction out of the reaction system.
滴下終了後さらに５分間同温度に保持した。After the dropwise addition was completed, the same temperature was maintained for an additional 5 minutes.
環化縮合終了後反応液を冷却し、それに１０％苛性ソー
ダ水溶液４００ｇを加え、攪拌下に６時間Ｉ！ｌｆ！
Ｒ水浴上でアルカリ処理した。冷却後水層を１０％酢酸
でｐＨ７〜７．５に調整し、析出した結晶をｐ取、水洗
後乾燥させて結晶２７．５９ （原料マロネートよりの
１ｉｌ収率８６％）をえた。After the cyclization condensation was completed, the reaction solution was cooled, 400 g of 10% caustic soda aqueous solution was added thereto, and the mixture was stirred for 6 hours! lf!
Alkali treatment was carried out on R water bath. After cooling, the aqueous layer was adjusted to pH 7 to 7.5 with 10% acetic acid, and the precipitated crystals were collected, washed with water, and dried to obtain crystals 27.59 (yield of 1 il from raw malonate: 86%).
えられた結晶をジメチルホルムアミド−エタノール混合
溶媒を用いて再結晶させ、精製した１−エチル−６−フ
ルオ四−１，４−ジヒドロー４−オキソ−７−（１−ピ
ペラジニル）−１，８−す７チリジンー６−カルボン酸
２７．２ｇ（原料マロネートよりの収率８２％）をえた
。The obtained crystals were recrystallized using a dimethylformamide-ethanol mixed solvent to obtain purified 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8- 27.2 g of 7-tylidine-6-carboxylic acid (yield 82% from the raw material malonate) was obtained.
えられた化合物の融点測定、ＭＳスペクトル分析を行な
った結果を以下に示す。The results of melting point measurement and MS spectrum analysis of the obtained compound are shown below.
融 点：２２０〜２２４°ＯMelting point: 220-224°O
Claims (1)
ヒドロ−４−オキソ−７−（４−エトキシカルボニル−
１−ピペラジニル）−１，８−す７チリジンー６−カル
ボンａ Ｂｌ’２キレート化合物。 ２ 式（ＩＩ） ： であられされるジエチル−Ｎ−エチル−Ｎ−（２−（４
−エトキシカルボニル−１−ピペラジニル）−６−フル
オロ−６−ピリジルコアミノメチレンマロネートを三フ
ッ化ホウ素および（または）三フッ化ホウ素錨体を用い
て溶媒の存在下または非存在下に加熱環化縮合させるこ
とを特徴とする式（Ｉ）： であられされる１−エチル−６−フルオロ−１，４−ジ
ヒドロ−４−オキソ−７−（４−エトキシカルボニル−
１−ピペラジニル）−１，８・−ナフチリジン−３一カ
ルボン酸ＥＦ２キレート化合物の製造法。 ６ 前記式（Ｉｔ）であられされる化合物と溶媒とを混
合、加熱し、これに三フッ化ポウ素および（または）三
フッ化ホウ素錯体を加える特許請求の範囲第２項記載の
方法。 ４ 前記式（ＩＩ）であられされる化合物、三フッ化ホ
ウ素エーテル錯体および溶媒を室温付近で混合し、その
混合物をそれとは別に加熱された溶媒中に加える特許請
求の範囲第２項記載の方法。 ５ 前記溶Ｗ カシフェニルエーテル、ジフェニルま
たは両番の混合物である特許請求の範囲第２項、第６項
または第４項記載の方法。 ６ 式（ｎ）： であられされる化合物奈三フッ化ホウ素および（または
）三フッ化ホウ素錨体を用いて加熱環化縮合させて、式
（■）： であられされるキレート化１，８−ナフチリジン誘導体
を製造し、つぎにそれを加水分解することを特徴とする
式（［０： であられされる１−エチル−６−フルオロ−１，４−・
クヒドロー４−オキソ−７−（１−ピペラジニル）−１
，８−す７チリジンー６−カルボン酸の製造法。[Claims] 1 Formula (I): 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethoxycarbonyl-
1-piperazinyl)-1,8-su7tyridine-6-carbon a Bl'2 chelate compound. 2 Formula (II): diethyl-N-ethyl-N-(2-(4
-ethoxycarbonyl-1-piperazinyl)-6-fluoro-6-pyridylcoamino methylene malonate is heated to a ring using boron trifluoride and/or a boron trifluoride anchor in the presence or absence of a solvent. 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethoxycarbonyl-
A method for producing a 1-piperazinyl)-1,8-naphthyridine-3 monocarboxylic acid EF2 chelate compound. 6. The method according to claim 2, wherein the compound represented by the formula (It) and a solvent are mixed and heated, and boron trifluoride and/or a boron trifluoride complex are added thereto. 4. The method according to claim 2, wherein the compound represented by formula (II), the boron trifluoride ether complex, and the solvent are mixed at around room temperature, and the mixture is added to a heated solvent separately. . 5. The method according to claim 2, 6, or 4, wherein the solution W is casiphenyl ether, diphenyl, or a mixture of both. 6 A compound formed by the formula (n) is heated and cyclized using boron trifluoride and/or a boron trifluoride anchor to form a chelate 1,8 formed by the formula (■): - preparing a naphthyridine derivative and then hydrolyzing it, characterized in that the formula ([0: 1-ethyl-6-fluoro-1,4-
Kuhydro 4-oxo-7-(1-piperazinyl)-1
, 8-su7tyridine-6-carboxylic acid production method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57191594A JPS5980683A (en) | 1982-10-30 | 1982-10-30 | 6-fluoro-1,8-naphthyridine derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57191594A JPS5980683A (en) | 1982-10-30 | 1982-10-30 | 6-fluoro-1,8-naphthyridine derivative and its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS5980683A true JPS5980683A (en) | 1984-05-10 |
Family
ID=16277231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57191594A Pending JPS5980683A (en) | 1982-10-30 | 1982-10-30 | 6-fluoro-1,8-naphthyridine derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5980683A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4871849A (en) * | 1985-12-09 | 1989-10-03 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | 1-Methylamino-quinoline-carboxylic acid derivatives |
| US4981966A (en) * | 1985-12-09 | 1991-01-01 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Process for the preparation of quinoline carboxylic acids |
| US5091530A (en) * | 1987-04-08 | 1992-02-25 | Chinoin Gyogyszer- Es Vegyeszeti Termekek Gyara Rt. | Baron chelates of quinoline carboxylic acids |
| JP2009030873A (en) * | 2007-07-26 | 2009-02-12 | Sanyo Electric Co Ltd | Storage |
-
1982
- 1982-10-30 JP JP57191594A patent/JPS5980683A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4871849A (en) * | 1985-12-09 | 1989-10-03 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | 1-Methylamino-quinoline-carboxylic acid derivatives |
| US4981966A (en) * | 1985-12-09 | 1991-01-01 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Process for the preparation of quinoline carboxylic acids |
| US5091530A (en) * | 1987-04-08 | 1992-02-25 | Chinoin Gyogyszer- Es Vegyeszeti Termekek Gyara Rt. | Baron chelates of quinoline carboxylic acids |
| JP2009030873A (en) * | 2007-07-26 | 2009-02-12 | Sanyo Electric Co Ltd | Storage |
| US8220888B2 (en) | 2007-07-26 | 2012-07-17 | Sanyo Electric Co., Ltd. | Storage with a symmetric hinge assembly |
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